Huntington’s disease

Aileen K. Ho

Introduction

Huntington’s disease (HD), a rare and progressive inherited neurological disorder that manifests in the classic triad of motor, cognitive and neuropsychiatric features, usually strikes between the third and fifth decade of life. Remorselessly, over a period of approximately 15-20 years, motor impairment, cognitive loss and neuropsychiatric changes manifest in the patient so that virtually no aspect of life is left untouched by the ravages of this disease. There is currently no tangible evidence for disease-modifying treatment, nor is there any means of delaying disease onset or significantly ameliorating the course of the disease. Purely symptomatic treatment can be of some utility in this complex condition. The fear and stigma associated with HD poses an additional burden to patients and their wider family circle when faced with the spectre of this monogenetic disease that has an inevitably fatal prognosis.

Prevalence

HD occurs worldwide affecting between 4 and 8 people in every 100,000 in Western populations, with a lower prevalence rate in Asian and African ethnicities (Harper, 1992). With the identification of the HD gene in 1993 and hence the availability of genetic testing to determine the length of the causative CAG (cytosine-adenine-guanine) expansion, it has been possible to conclusively diagnose HD. This is particularly helpful in cases of de now patients with no known family history, where there may have been previously unknown intermediate or low penetrance alleles. With the availability of genetic testing, and despite its low uptake by at risk individuals, there have since been indications of a rise in prevalence figures up to 13.7 per 100,000 (Fisher & Hayden, 2014); however, the pattern of Caucasian prominence remains.

Clinical vignette

This vignette follows the story of Mariella, who grew up knowing that her grandmother was always a bit different and had rather strange mannerisms. When she was in secondary school, Mariella’s father’s behaviour started to become rather uncharacteristic and erratic. He too became restless and clumsy, demonstrating odd jerks and twitches as he moved. This was when she learnt from her parents that her father and grandmother both had Huntington’s disease, and that she had a 50% chance of inheriting the faulty HD gene. As Mariella started university it was clear that her grandmother’s condition was deteriorating. Mariella grappled with whether or not to undergo genetic testing, and decided she did not want to know her status as there was no treatment available. Not knowing was better than facing the knowledge of an unfavourable test result. Instead, she concentrated on living her life as normally as she could. She embarked on a successful career in finance, working globally, and returned home to get married in her early thirties. By now her parents had separated, and her father was about to enter a care home as he was severely affected by HD. Mariella had always been open about being at risk for HD, and her husband had been aware of this for many years. As they were hoping to start a family, Mariella felt it was the right time to get tested, and they went for genetic counselling together. This was the same process her younger sister, who tested negative for the HD gene, had gone through several years previously. Mariella only found out about this recently at their grandmother’s funeral. When her test results came, they revealed that Mariella did indeed carry the HD gene. She was rather taken aback by this bad news although she had understood there was an equal chance for either outcome. The reality of living with the knowledge of developing HD in the future affected her more than she had anticipated. She had chosen to be tested to find certainty, but was still riddled by (different) uncertainties and questions. She struggled to come to terms with living with her gene positive presymptomatic status and its future implications. Her mood was affected as she became increasingly withdrawn. She felt clumsier than usual and work was more of a struggle as she felt less sharp mentally. Sleep was difficult as many worrying thoughts charged through her mind as she wondered if she was starting to experience early signs and symptoms of HD. This persisted over several years and eventually she decided to stop working due to the stress of her demanding role. She had not told anyone about her genetic status apart from her husband, who was with her during the genetic testing process. Mariella did consider preimplantation genetic diagnosis and in vitro fertilisation to avoid passing on the HD mutation, but then fell pregnant naturally and gave birth to a baby boy. At that point, her father was no longer able to communicate clearly and relied on a feeding tube for nutrition.

The story pauses at Mariella’s father’s fiineral where she is still feeling the weight of the multiple different roles the disease had enforced on her - a presymptomatic (or possibly prodromal) gene positive HD carrier, mother of a child who is at a 50% risk of the same disease, and as the daughter of a man who valiantly fought an all-consuming disease for two decades. As Mariella tripped slightly on the stairs at the event, she felt the collective gaze of the entire clan on her, magnifying her self- consciousness, as she navigated her way around the buffet table trying to balance her meal while making conversation. On reflection, her mind felt slow and foggy, a far cry from her former high-flying executive self of five years ago when she thrived on juggling multiple fast-moving tasks. In contrast, she often felt anxious and on edge, having lost the motivation to do all but what was absolutely necessary for her and her young family.

Diagnostic considerations

A diagnosis of HD is based on neurological presentation, and is confirmed after a positive genetic test for the presence of the CAG expansion in the huntingtin gene. This occurs in the context of a family history of HD, and also after excluding other possible causes. A firm diagnosis is currently made on the basis of the motor signs and symptoms (Reilmann, Leavitt & Ross, 2014), where extraneous involuntary movement is present, often together with slowed voluntary movement that may be reduced in range and/or fluency of execution. Before overt onset based on these motor changes, individuals do not have manifest disease and are not considered symptomatic. However, there is something of a false dichotomy here, as very gradual motor changes over a period of time mean that pinpointing an exact moment of onset is often not entirely feasible, and that onset may be a matter of degree and with an increasing level of confidence over time.

Discernible changes in cognitive function, mood, and/or behaviour may in fact predate motor onset. Often, these changes may manifest before clear motor signs and symptoms emerge. These cognitive and behavioural changes are less straightforward to interpret and to attribute directly to the disease, as they can be more subjective and also interact dynamically with the broader context of life. Nevertheless, there is a pathophysiological basis for these emotional, cognitive and behavioural changes in HD and they can have a substantial impact on individuals and their families many years prior to the motor symptoms that are a defining point for diagnosis.

Within the premanifest phase, a further distinction can be drawn using more sensitive ways of examining motoric and cognitive facets of behaviour. The advent of genetic testing - such as Predict-HD (Patrick, Curtis, Engelberg, Nielsen & McCown, 2003) and Track-HD (Tabrizi et al., 2012) - and cohorts of premanifest individuals who are amenable to neuroimaging research and more detailed behavioural studies, has shown that a transitory prodromal period exists before manifest disease can be detected. This period is marked by small changes in psychomotor tasks such as the Symbol Digit Modalities Test, the Stroop word-reading task, quantitative motor measures such as hand tap variability, in addition to structural brain imaging. These are subtle prodromal signs and symptoms that may not be detected in everyday life, nor may they hinder functional performance, but are early indicators of change that may be linked to under par performance.

Better understanding of the emergence of subtle non-motor changes has led to suggestions of more nuanced and expanded diagnostic criteria (Reilmann et al., 2014). Nevertheless, disease onset is currently defined by motor onset, and the presence of motor symptoms remains the basis for a diagnosis of clinically manifest disease.

The gradual unfolding of motor, cognitive and behavioural changes that culminate in manifest HD means that in reality, diagnosis and the communication of diagnosis is not clear cut (McCusker & Loy, 2017). The onset of HD, or indeed its progression across stages, occurs on a cumulative spectrum of confidence rather than manifesting as discrete events. This is usually reflected in clinical care where a considered approach is often taken reflecting the person’s individual circumstances. Clinical assessment and discussions over several periodic consultations serve as a means for reflection and review, and allow individuals time and space to process and adjust to the conceptual and practical aspects of progression in HD. Therefore, a gradual process of disclosure of diagnosis and progression can be helpful in clinical management and care.

 
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